Vascular remodeling and perivascular infiltration, occurring mostly in the small to mid-sized pulmonary arterioles (<500 μm), are critical events of most forms of pulmonary hypertension (PH) and frequently leads to progressive functional decline in patients despite treatment with currently available therapies. Although the exact mechanisms leading to the onset and progression of PH are still largely unclear, a complex interplay between pulmonary endothelial dysfunction and inflammation is strongly suspected to influence the development of the disease (Huertas et al, Circulation, 2014, 129: 1332-1340).
Prostacyclin analogs such as Epoprostenol are indicated in PH treatment. However it is administered via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Moreover, prostacyclin analogs are unstable, their half-life is of 3 to 5 minutes and the infusion has to be continuous since interruption can be fatal. Due to the lack of tolerability, the skilled artisan tends to treat PH with endothelin receptor antagonists (ERAs) as described in patent application US2004/102361 or phosphodiesterase type 5 (PDE5) inhibitors as described in patent application WO2009/115235.
Most of these drugs constitute palliative care and cannot cure PH. Indeed these drugs taken separately only have a limited action and act mainly on the balance between vasoconstriction and vasodilatation that constituted only one component of this complex and multifactorial disease.
Thus, there is a need to discover and/or develop new, better-tolerated and more powerful therapeutic small molecules for treating PH. In addition, compounds able to control different causal-mechanisms deregulated in PH (for example, the excessive proliferation/survival of pulmonary vascular cells and/or the abnormal inflammation/autoimmunity) would be a major step forward curing PH.
The present invention demonstrates that compounds having the Formula I:
(wherein Ar, R1 and R2 are as defined below) are effective to treat PH at a low concentration in a rat model of PH due to their action on both lung inflammation and pulmonary vascular cell proliferation/survival.